The virus causing the acquired immunodeficiency syndrome (AIDS) is known by different names, including T-lymphocyte virus III (HTLV-III) or lymphadenopathy-associated virus LAV) or AIDS-related virus (ARV) or human immunodeficiency virus (HIV). Up until now, two distinct families have been identified, i.e. HIV-1 and HIV-2. Hereinafter, HIV will be used to generically denote these viruses.
One of the critical pathways in a retroviral life cycle is the processing of polyprotein precursors by retroviral protease. For instance, during the replication cycle of the HIV virus, gag and gag-pol gene transcription products are translated as proteins, which are subsequently processed by a virally encoded protease to yield viral enzymes and structural proteins of the virus core. Most commonly, the gag precursor proteins are processed into the core proteins and the pol precursor proteins are processed into the viral enzymes, e.g., reverse transcriptase and retroviral protease. Correct processing of the precursor proteins by the retroviral protease is necessary for the assembly of infectious virions, thus making the retroviral protease an attractive target for antiviral therapy. In particular for HIV treatment, the HIV protease is an attractive target.
Several protease inhibitors are on the market or are being developed. Hydroxyethylamino sulfonamide HIV protease inhibitors, for example 4-aminobenzene hydroxyethylamino sulfonamides, have been described to have favourable pharmacological and pharmacokinetic properties against wild-type and mutant HIV virus. Amprenavir is a commercially available exponent of this 4-aminobenzene hydroxyethylamino sulfonamide class of protease inhibitor. A process for the synthesis of amprenavir is described in WO99/48885 (Glaxo Group Ltd.).
4-aminobenzene hydroxyethylamino sulfonamides may also be prepared according to the procedures described in EP 715618, WO 99/67417, U.S. Pat. No. 6,248,775, and in Bioorganic and Chemistry Letters, Vol. 8, pp. 687-690, 1998, “Potent HIV protease inhibitors incorporating high-affinity P2-ligands and (R)-(hydroxyethylamino) sulfonamide isostere”, all of which are incorporated herein by reference. In particular, (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[[(4-aminophenyl) sulfonyl](isobutyl)amino]-1-benzyl-2-hydroxypropylcarbamate, herein referred to as compound of formula (6), and methods for its preparation may be found disclosed in WO99/67417 (USA, The Secretary, Dpt. of Health and Human Services), and in PCT/EP03/50176 (Tibotec N.V.).
WO03/057665 (Ajinomoto KK) relates to a process for producing crystals of benzenesulfonamide derivatives. In particular, it provides a crystallization for (2R,3S) -N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-amino-benzensulfonamide, which is an intermediate of interest for the preparation of (3R,3aS,6aR)-hexahydrofuro [2,3-b]furan-3-yl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-hydroxypropylcarbamate. This intermediate of interest is obtained according to the disclosure by departing from a (2S,3S)-3-benzyloxycarbonylamino-1,2-epoxy-4-phenylbutane, to which isobutylamite is reacted, followed by coupling of p-nitro-benzenesulfonylchloride to yield (2R,3S)-N-(3-benzyloxycarbonylamino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-nitrobenzenesulfonamide, which is simultaneously reduced and deprotected to obtain the intermediate of interest. In particular, the route employs a benzyloxycarbonyl (Cbz or Z) as the amino protecting group of the core molecule. It is observed that the simultaneous reduction of the nitro moiety and Cbz deprotection in (2R,3S)-N-(3-benzyloxycarbonylamino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-nitrobenzenesulfonamide results in a highly exothermic reaction. Exothermic reactions, if possible, should be avoided or limited to its minimum extent, as they are more difficult for controlling reaction temperatures, i.e. when the reaction temperature would be too low, the reaction rate is small and a long time is required; when the reaction temperature would be too high, the reaction rate is too large and insufficient mixing occurs, inviting nonuniform reaction, deterioration (burning) of the product formed, or unwanted side reactions may take place with the result that product selectivity is decreased. On the other hand, it is also observed that the catalytic reduction disclosed in WO03/057665 does not include an acid treatment. In the absence of an acid treatment, it is expected that the catalyst employed during reduction and Cbz deprotection will be poisoned with the sulfur from p-nitrobenzenesulfonyl-chloride. A poisoned catalyst will inevitably result into the appearance of side-products thus decreasing product selectivity.
In order for a chemical route to be suitable for industrial scale, it should produce compounds in acceptable yields and purity while being easy and simple to carry out, as well as cost effective. As such, there has been found a new process for the synthesis of compound of formula (6) which is amenable for industrial scale.

In particular, the present invention provides a convenient process for the production of compound of formula (6) and intermediates, addition salts, polymorphic and/or pseudopolymorphic forms thereof at industrial scales. More in particular, the present invention encompasses a suitable route for the synthesis of compound of formula (6) which further benefits from an improved and cost-effective crystallization of (2R,3S)-N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-amino-benzenesulfonamide with acceptable purities and yields. Even more in particular, the present invention presents separate reduction and deprotection reactions encompassing an acid treatment, all resulting in a more controllable, selective and cost-effective process.
In one embodiment, the present invention provides an improved crystallization employing pH and concentration controls in defined ranges, while the crystallization by WO03/057665 only makes mention of heating the solution in polar solvent in order to improve the yield, or heating the solution (30-80° C.) in order to dissolve the crystals present in the polar solvent solution in order to improve purification.
The present invention has the further advantage of using commercially available starting material, such as a 1-oxiranyl-2-phenyl-ethyl-carbamic acid tert-butyl ester. Further, the precursor of compound of formula (6), i.e. (2R,3S)-N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-amino-benzenesulfonamide or compound of formula (5), may be produced as a one-pot procedure which results in an efficient utilization of the reactor and the omission of intermediate purification steps. The reagents further used in said process are safe and available in bulk. Furthermore, each step of said method is performed at controllable conditions and provides with the desired compound in optional yields. Moreover, each step of said process is performed stereoselectively, which allows the synthesis of pure stereoisomeric forms of the desired compounds.
Other objects and advantages of the present invention will become apparent from the following detailed description taken in conjunction with the accompanying examples.
EP0754669 (Kaneka Corporation) describes processes for producing alpha-halo ketones, alpha-halohydrins and epoxides; EP1029856 (Kaneka Corp.) discloses a process for the preparation of (2R,3S)-3-amino-1,2-oxirane; and EP1067125 also by Kaneka Corporation relates to a process for the preparation of threo-1,2-epoxy-3-amino-4-phenylbutane. EP774453 (Ajinomoto Co., Inc.) describes a process for producing 3-amino-2-oxo-1-halogenopropane derivatives. In WO01/12599 (Samchully Pharm Co. Ltd.) there is described new ethylaziridine derivatives and their preparation methods. WO01/46120 (Aerojet Pine Chemicals LLC) discloses an improved preparation of 2S,3S-N-isobutyl-N-(2-hydroxy-3-amino-4-phenylbutyl)-p-nitrobenzenesulfonylamide hydrochloride and other derivatives of 2-hydroxy-1,3-diamines. In WO96/28418 (G. D. Searle & Co., Inc.) there are disclosed sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors. WO94/04492 (G. D. Searle & Co., Inc.) discloses alpha- and beta-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors. WO97/21685 (Abbott) discloses the preparation of peptide analogues as retroviral protease inhibitors. WO94/05639 (Vertex Pharmaceuticals) describes sulfonamide inhibitors of HIV-1 aspartyl protease.